Detailed kinetic study of the enzyme, adenylate cyclase, has been underway for one year. To a lesser extent work has begun on the enzyme guanylate cyclase and the cyclic nucleotide phosphodiesterases. These enzymes are extremely important enzymes in the expression by a cell of "differentiated" behavior i.e. they regulate reponse to hormones, response of the adrenergic and cholinergic nervous systems, and have a strong influence on rates of cell division, at least in vitro. As such, the kinetic behavior of these enzymes and the manipulation of their kinetic behavior through possible pharmacological agents has become a very important area of research. The proposed work deals with an effort to gain sufficient knowledge of the detailed mechanisms of catalysis, for each of the enzymes mentioned above, to achieve a two-fold objective: 1. to prevent the mistaking of simple enzyme kinetic phenomena for control or regulatory phenomena; 2. to allow design of specific agents for selectively inhibiting either adenylate cyclase, guanylate cyclase, or the cyclic nucleotide phosphodiesterase(s), in each case without affecting any of the other enzymes; preferably to find inhibiting agents which can also pass through the intact cell membranes to do their specific inhibiting, allowing in situ probes of important cellular regulatory phenomena. A promising group of agents have been found, the phosphate diesters, which selectively inhibit adenylate cyclase without inhibiting guanylate cyclase or the cyclic nucleotide phosphodiesterases. The implications of these inhibitors for enzyme mechanism, for application to medical problems, and as probes of cellular regulatory phenomena will be studied. It is also proposed to seek for a class of inhibitors with the same behaviors for guanylate cyclase.